DNA mismatch repair is essential to the maintenance of genome integrity and not surprising, loss of normal mismatch repair is a feature of many cancers. Inherited defects in DNA mismatch repair dramatically increase an individual's risk of developing cancer. Somatic inactivation of a mismatch repair gene, either as a result of mutation or epigenetic changes, confers a mutator phenotype and directly contributes to the accumulation of mutations in the cancer cell. A substantial fraction of endometrial carcinomas, the most common gynecologic malignancy in the US, have defective DNA mismatch repair. Aberrant methylation of the MLH1 promoter is associate with defective DNA mismatch repair in the majority of these cancers. However, an estimated 5 percent of all endometrial cancer patients have an inherited mismatch repair gene defect. This is a proposal for a multidisciplinary study to determine the role that defective DNA mismatch repair plays in endometrial tumorigenesis. It relies upon established collaborations between, and the joint expertise of molecular and medical geneticists, pathologist and gynecologic oncologist. Specific aims are: 1) To define the penetrance and expressivity of inherited defects in DNA mismatch repair in kindreds ascertained through endometrial cancer probands. A combination of molecular and conventional family/medical history studies will be undertaken to determine the spectrum of cancers that develop as a consequence of inherited MSH2 and MLH1 mutations. The penetrance of mutations will be determined by performing mutation analysis in at-risk relatives of endometrial cancer patients in whom germline mutations are identified. 2) To elucidate the temporal relationship between loss of normal DNA mismatch repair and accumulation of lesions in the PTEN and TP53 tumor suppressor and the KRAS2 proto-oncogene. Hyperproliferative precursors of endometrial carcinoma will be investigated to define the timing of molecular events that underlie the phenotypic progression in endometrial tumorigenesis and to determine the clonality of synchronous hyperplasia and carcinoma. 3) To define the relationship between DNA mismatch repair in endometrial cancers and a more global hypermethylation state. Patterns of CpG island methylation will be compared among groups of tumors with and without apparent defects in DNA repair.